Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Abstract

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

“…The ASL modifications (c)t 6 A and mcm 5 (s 2 )U, found in yeast tRNAs respectively at positions 37 and 34, are critical for correct pre-structuring of the ASL [13][14][15][16][17]. Severe diseases in humans [18][19][20][21][22] and very similar phenotypes in yeast S. cerevisiae [3,29,37] are observed as a result of deficiencies in both these modifications. The sua5 elp3 mutant (lacking both t 6 A and mcm 5 U modifications), is viable in the YPD medium but cannot grow in the presence of various exogenous stressors such as elevated temperature, diamide or alternative carbon sources.…”

“…Early structural studies showed that t 6 A is crucial for the prevention of U33-A37 pairing, thus stabilizing the anticodon open-loop configuration, and that both modifications are critical for correct pre-structuring of the ASL [13][14][15][16][17]. Deficiencies in both these modifications lead to severe neurological diseases [18][19][20][21][22], and the yeast Saccharomyces cerevisiae has been a long-standing model to study their synthesis and function [23][24][25][26][27][28]. In yeast, t 6 A is found at position 37 of tRNAs that decode ANN codons and is further modified to ct 6 A in several tRNAs such as tRNA Lys UUU [29,30].…”

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

“…MLX and YBX-1 are known glycolytic shift regulators—controlling retrograde mitochondrial signaling to the nucleus, expression of glycolytic and lipogenic genes, and integrating PI3K/AKT signaling to glycolysis (Amal et al, 2015; Billin and Ayer, 2006; Butow and Avadhani, 2004; Diolaiti et al, 2015; Lasham et al, 2013; Sans et al, 2006; Stoltzman et al, 2008; Suresh et al, 2018; Xu et al, 2017). MED27, MRPL12 and ELP5 further contribute to these activities (Alexander et al, 2013; Catarina et al, 2014; Close et al, 2012; Fisher, 2018; Frei et al, 2005; Hawer et al, 2018; Rapino and Close, 2018). The transition to a more proliferative phenotype is highlighted by the activation of BUD31, YBX-1, SARNP, TARBP2, SIVA1 , and PHB.…”